RGD Reference Report - Loss of metabotropic glutamate receptor 2 escalates alcohol consumption. - Rat Genome Database

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Loss of metabotropic glutamate receptor 2 escalates alcohol consumption.

Authors: Zhou, Zhifeng  Karlsson, Camilla  Liang, Tiebing  Xiong, Wei  Kimura, Mitsuru  Tapocik, Jenica D  Yuan, Qiaoping  Barbier, Estelle  Feng, Austin  Flanigan, Meghan  Augier, Eric  Enoch, Mary-Anne  Hodgkinson, Colin A  Shen, Pei-Hong  Lovinger, David M  Edenberg, Howard J  Heilig, Markus  Goldman, David 
Citation: Zhou Z, etal., Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16963-8. doi: 10.1073/pnas.1309839110. Epub 2013 Sep 30.
RGD ID: 149735328
Pubmed: PMID:24082084   (View Abstract at PubMed)
PMCID: PMC3800985   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1309839110   (Journal Full-text)

Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 (-/-) mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target.

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased synaptic depression  IAGP 149735328compared to NP/IusmRGD 
Objects Annotated

Strains
Iusm:P  (alcohol-preferring)


Additional Information